This program is directed toward the detailed understanding of tissue factor, the central initiator of blood coagulation. Tissue factor, a transmembrane protein, functions as an essential activator of an enzyme and enzyme precursor that circulate in the blood, factors VIIa and VII. Together, the form a specific enzyme that starts the coagulation of blood by activating two other blood proteins. Recent evidence indicates that tissue factor is implicated not only in blood coagulation but also in thrombosis, which is a clot that forms inside a blood vessel. This problem is being approached using techniques involving computer simulations, physical chemistry, enzyme kinetics and molecular biology. A new finding suggests that tissue factor may also be involved in the spread of cancer. Accordingly, one project is designed to test this hypothesis by manipulating the tissue factor content of cells that in their native state are only slightly metastatic. We also are interested in the detailed structure of tissue factor in complex with the enzyme, factor VIIa and the next protein involved in the coagulation scheme, factor X. These projects involve research laboratories at Mt. Sinai School of Medicine and Yale University. There are four research teams in this program which are collaborating on a series of experiments that are intended to answer several fundamental questions regarding blood coagulation and thrombosis.